5. Multiple Mitochondrial Dysfunction Syndrome (MMDS)
Multiple mitochondrial dysfunction syndrome (MMDS) describes a class of fatal mitochondrial diseases caused by mutations in proteins involved in Fe-S cluster biogenesis and trafficking. To date, four types of MMDS have been identified: namely, MMDS1 due to mutations on Nfu,41 MMDS2 for mutations with BOLA3,41b, 42 MMDS3 with mutations on Iba57,43 and MMDS4, with mutations on IscA2.44 Recently, an IscA1 variant has been described that results in MMDS-like symptoms, which may expand the class of disorders.45 All MMDS patients exhibit similar symptoms that include metabolic acidosis with hyperglycemia, and deficiency of respiratory complexes and lipoic acid bound enzymes, such as pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH).41f, 46 Lipoate biogenesis relies on the mitochondrial [4Fe-4S] enzyme lipoate synthase (LIAS).
For MMDS1, five patients have been described with a homozygous mutation in Nfu (p.Arg182Gln), where the mutation is close to a splice site and results in skipping of exon 6 and no detectable protein levels.46 Most other patients were described with a homozygous mutation (p.Gly208Cys) that affects an amino acid close to a highly conserved Fe-S cluster binding domain of the Nfu protein. This mutation does not affect protein levels but does impair Fe-S cluster binding and transfer, most likely due to a perturbed monomer-dimer equilibrium that limits cellular reconstitution of Nfu.41f, 47 Most recently, a study of patients with the heterozygous gene for Nfu, one with the altered splice site or with the Gly208Cys missense mutation and the native allele, has revealed that low levels of the wild type Nfu mRNA were produced, which yielded sufficient functional LIAS to avoid lipoic acid deficiency, but the wild type transcripts were insufficient to support functional respiratory complex II.41d
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In the case of MMDS2, 6 different patients have been identified with mutations on BOLA3.41b, 42 The first patient demonstrated a single base pair duplication that produced a frameshift with a premature stop codon and therefore loss of the full length protein.41b Two other patients have been characterized as having a missense mutation at a highly conserved residue (p.Ile67Asn)42b that could affect the overall protein fold based on the solution NMR structure of human BOLA3.48 The remaining three patients all demonstrated a truncating mutation of eight amino acids upstream of the first truncating mutation.42a To date, the molecular role of BOLA3 remains to be elucidated; however the availability of an NMR structure48-49 with additional biochemical characterization will provide increasing understanding of its role in MMDS.
Similar to BOLA3 in MMDS2, a wide variety of mutations on Iba57 have been identified for MMDS3. Initial reports described different patients with a range of phenotypes. The first case resulted in the most severe condition caused by a missense mutation (p. Gln314Pro) that appeared to result in protein misfolding with subsequent degradation to concentrations below critical levels.43a The mildest phenotype was observed in a patient with an Iba57 mutation that resulted in reduced mRNA levels because of aberrant splicing and a frameshift mutation that yielded a truncated form of Iba57.43c The intermediate phenotype of MMDS3 was due to a mutation on Iba57 that drastically reduced its ability to function in Fe-S biogenesis with diminished levels of [4Fe-4S] clusters.43b Most recently, four additional mutations on Iba57 have been observed with generally the same symptoms and phenotypes.43d The prevalence of such diverse mutations on Iba57 that all result in MMDS3 makes prediction of the disease difficult, based on genetic information, and strengthens the need for further biochemical characterization of Iba57 to understand why so many possible causes of the disease exist.
MMDS4 was the most recent class to be discovered, with six patients exhibiting a missense mutation (p.Gly77Ser) on IscA2, which is located in a highly conserved cluster binding domain. However, the exact effect of the mutation is unclear, since mRNA levels were not significantly impacted.44 Interestingly, patient fibroblasts also showed lower levels of IscA1 and Iba57 than control fibroblasts.44 How this mutation results in lower protein levels of these partner proteins remains unclear. Similarly, an IscA1 mutation (p.Glu87Lys) has been implicated in causing MMDS-like symptoms, which may result in a new class of the disorder, as one patient has been found with this mutation that is expected to lead to protein instability due to loss of a conserved salt-bridge.45
The class of MMDS disorders describes a newly discovered disease condition and further details on how mutations in key Fe-S biogenesis proteins influence cellular function, and their roles that result in disease, need to be determined in order to fully aid patients.
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